The primary goal of this study has been to explore the application of new biochemical methodologies to human genetic diseases affecting the central nervous system. A concentrated effort has been made with the techniques of high resolution two-dimensional electrophoresis (2DE) autoradiography and ultra-sensitive silver staining. Continued efforts to develop more reliable staining methods has resulted in a photodevelopment silver stain which permits visualization of proteins 10 minutes after electrophoresis. Initial studies utilizing these technics involved a disorder with known biochemical alterations, the Lesch-Nyhan syndrome. Currently, we are investigating a disease with a suspected genetic basis, familial Alzheimer's disease. Large multigenerational pedigrees have been utilized. These pedigrees serve a dual role, they permit a greater chance to establish trait specific markers than smaller families, and they also serve as a resource in the development of a human genome map based on polymorphic markers. The establishment of a human genome map based on polymorphic marker loci will be an invaluable aid in investigations of any disease which contains a genetic component. The protein polymorphisms identified in this study will complement the DNA polymorphisms which are being identified in other laboratories. We have established cell lines from the individuals in the pedigrees under investigation. These cells are permitting investigations of additional paradigms for these diseases, such as the possible role for viral genes, which have been integrated into the human genome, and the use of specific DNA probes. A number of diseases involving the central nervous system (CNS) have been included in a survey utilizing the high resolution 2DE with silver staining to search for alterations in cerebrospinal fluid (CSF) proteins. Altered CSF protein patterns have been found in Herpes Encephalitis, Creutzfeldt-Jakob disease, Parkinson's disease, multiple sclerosis and in 40% of the shizophrenics examed.